1-108929693-A-G

Variant names:

• chr1-108929693-A-G
• rs138132875
• NM_001377458.1:c.*2854T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_Moderate BP6_Very_Strong

The NM_001377458.1(CLCC1):​c.*2854T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000402 in 1,612,714 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CLCC1 NM_001377458.1 3_prime_UTR
• Scores: Splicing: ADA: 0.7503
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.120
• Publications: 0 publications found

Genes affected

CLCC1 (HGNC:29675): (chloride channel CLIC like 1) Predicted to enable chloride channel activity. Predicted to be involved in chloride transport. Located in endoplasmic reticulum and mitochondria-associated endoplasmic reticulum membrane. Implicated in retinitis pigmentosa 32. [provided by Alliance of Genome Resources, Apr 2022]

GPSM2 (HGNC:29501): (G protein signaling modulator 2) The protein encoded by this gene belongs to a family of proteins that modulate activation of G proteins, which transduce extracellular signals received by cell surface receptors into integrated cellular responses. The N-terminal half of this protein contains 10 copies of leu-gly-asn (LGN) repeat, and the C-terminal half contains 4 GoLoco motifs, which are involved in guanine nucleotide exchange. This protein may play a role in neuroblast division and in the development of normal hearing. Mutations in this gene are associated with autosomal recessive nonsyndromic deafness (DFNB82). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

AKNAD1 (HGNC:28398): (AKNA domain containing 1) This gene encodes a protein which contains a domain found in an AT-hook-containing transcription factor. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2012]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• BP6: Variant 1-108929693-A-G is Benign according to our data. Variant chr1-108929693-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377458.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCC1	NM_001377458.1	MANE Select	c.*2854T>C		3_prime_UTR	Exon 13 of 13	NP_001364387.1
	GPSM2	NM_013296.5	MANE Select	c.1816-8A>G		splice_region intron	N/A	NP_037428.3
	CLCC1	NR_165299.1		n.5125T>C		non_coding_transcript_exon	Exon 15 of 15

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCC1	ENST00000369969.7	TSL:5 MANE Select	c.*2854T>C		3_prime_UTR	Exon 13 of 13	ENSP00000358986.3
	GPSM2	ENST00000264126.9	TSL:1 MANE Select	c.1816-8A>G		splice_region intron	N/A	ENSP00000264126.3
	CLCC1	ENST00000674992.1		n.*4327T>C		non_coding_transcript_exon	Exon 13 of 13	ENSP00000501696.1

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00789

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000558 AC: 139 AN: 249246 AF XY: 0.000459

Gnomad AFR exome AF: 0.00791

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000213 AC: 311 AN: 1460394 Hom.: 0 Cov.: 29 AF XY: 0.000180 AC XY: 131 AN XY: 726568

African (AFR) AF: 0.00813 AC: 272 AN: 33452

American (AMR) AF: 0.000291 AC: 13 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110846

Other (OTH) AF: 0.000331 AC: 20 AN: 60344

GnomAD4 genome AF: 0.00222 AC: 338 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00219 AC XY: 163 AN XY: 74482

African (AFR) AF: 0.00791 AC: 329 AN: 41568

American (AMR) AF: 0.000523 AC: 8 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00104 Hom.: 1

Bravo AF: 0.00272

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1816-8A>G in Intron 14 of GPSM2: This variant is not expected to have clinical s ignificance because it has been identified in 0.8% (29/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs138132875).

Jan 05, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Chudley-McCullough syndrome Benign:1

Jul 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GPSM2-related disorder Benign:1

Nov 16, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.66
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.75
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.54		Position offset: 8

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs138132875; hg19: chr1-109472315;