rs41286594

Positions:

chr2-96799647-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020184.4(CNNM4):c.1947C>T(p.Ser649Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,550,670 control chromosomes in the GnomAD database, including 449 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 24 hom., cov: 32)

Exomes 𝑓: 0.022 ( 425 hom. )

Consequence

CNNM4
NM_020184.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0001088

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -4.24

Variant links:

Genes affected

CNNM4 (HGNC:105): (cyclin and CBS domain divalent metal cation transport mediator 4) This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play a role in metal ion transport. Mutations in this gene are associated with Jalili syndrome which consists of cone-rod dystrophy and amelogenesis imperfecta. [provided by RefSeq, Feb 2010]

CNNM4 links:

CNNM4 (HGNC:):

CNNM4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-96799647-C-T is Benign according to our data. Variant chr2-96799647-C-T is described in ClinVar as [Benign]. Clinvar id is 261212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-96799647-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-4.24 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0154 (2347/152334) while in subpopulation NFE AF= 0.0226 (1537/68032). AF 95% confidence interval is 0.0217. There are 24 homozygotes in gnomad4. There are 1110 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CNNM4	NM_020184.4 linkuse as main transcript	c.1947C>T	p.Ser649Ser	splice_region_variant, synonymous_variant	5/7	ENST00000377075.3	NP_064569.3	Q6P4Q7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CNNM4	ENST00000377075.3 linkuse as main transcript	c.1947C>T	p.Ser649Ser	splice_region_variant, synonymous_variant	5/7	1	NM_020184.4	ENSP00000366275.2		Q6P4Q7-1
CNNM4	ENST00000496186.5 linkuse as main transcript	n.621C>T		splice_region_variant, non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes

AF:

0.0154

AC:

2341

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00528

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0219

Gnomad ASJ

AF:

0.00779

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0226

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0168

AC:

2627

AN:

156836

Hom.:

AF XY:

0.0168

AC XY:

1382

AN XY:

82492

show subpopulations

Gnomad AFR exome

AF:

0.00478

Gnomad AMR exome

AF:

0.0244

Gnomad ASJ exome

AF:

0.00644

Gnomad EAS exome

AF:

0.0000880

Gnomad SAS exome

AF:

0.0168

Gnomad FIN exome

AF:

0.00974

Gnomad NFE exome

AF:

0.0216

Gnomad OTH exome

AF:

0.0178

GnomAD4 exome

AF:

0.0220

AC:

30809

AN:

1398336

Hom.:

425

Cov.:

AF XY:

0.0220

AC XY:

15176

AN XY:

689792

show subpopulations

Gnomad4 AFR exome

AF:

0.00415

Gnomad4 AMR exome

AF:

0.0266

Gnomad4 ASJ exome

AF:

0.00731

Gnomad4 EAS exome

AF:

0.0000839

Gnomad4 SAS exome

AF:

0.0168

Gnomad4 FIN exome

AF:

0.0107

Gnomad4 NFE exome

AF:

0.0246

Gnomad4 OTH exome

AF:

0.0198

GnomAD4 genome

AF:

0.0154

AC:

2347

AN:

152334

Hom.:

Cov.:

AF XY:

0.0149

AC XY:

1110

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00531

Gnomad4 AMR

AF:

0.0220

Gnomad4 ASJ

AF:

0.00779

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0147

Gnomad4 FIN

AF:

0.0101

Gnomad4 NFE

AF:

0.0226

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.0198

Hom.:

Bravo

AF:

0.0151

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Jalili syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.11

DANN

Benign

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.11

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over