1-1916758-G-C

Variant names:

• chr1-1916758-G-C
• rs74773083
• NM_138705.4:c.260G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138705.4(CALML6):​c.260G>C​(p.Gly87Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00231 in 1,613,550 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G87V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (44 hom.)
• Consequence: CALML6 NM_138705.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.09

Genes affected

CALML6 (HGNC:24193): (calmodulin like 6) Predicted to enable calcium ion binding activity and enzyme regulator activity. Predicted to be involved in regulation of catalytic activity. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004542172).
• BP6: Variant 1-1916758-G-C is Benign according to our data. Variant chr1-1916758-G-C is described in ClinVar as [Benign]. Clinvar id is 783273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0121 (1843/152326) while in subpopulation AFR AF= 0.0419 (1741/41566). AF 95% confidence interval is 0.0402. There are 39 homozygotes in gnomad4. There are 852 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALML6	NM_138705.4	c.260G>C	p.Gly87Ala	missense_variant	Exon 4 of 6	ENST00000307786.8	NP_619650.2
CALML6	NM_001330313.2	c.209G>C	p.Gly70Ala	missense_variant	Exon 3 of 5		NP_001317242.1
CALML6	XM_005244729.4	c.326G>C	p.Gly109Ala	missense_variant	Exon 4 of 6		XP_005244786.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALML6	ENST00000307786.8	c.260G>C	p.Gly87Ala	missense_variant	Exon 4 of 6	1	NM_138705.4	ENSP00000304643.3
CALML6	ENST00000378604.3	c.209G>C	p.Gly70Ala	missense_variant	Exon 3 of 5	3		ENSP00000367867.3
CALML6	ENST00000462293.1	n.334G>C		non_coding_transcript_exon_variant	Exon 2 of 3	3
CALML6	ENST00000482402.1	n.1493G>C		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1837 AN: 152208 Hom.: 38 Cov.: 31

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

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: 0.000103

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00342 AC: 860 AN: 251110 Hom.: 15 AF XY: 0.00249 AC XY: 338 AN XY: 135824

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00129 AC: 1879 AN: 1461224 Hom.: 44 Cov.: 53 AF XY: 0.00111 AC XY: 805 AN XY: 726880

Gnomad4 AFR exome AF: 0.0450

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000486

Gnomad4 OTH exome AF: 0.00262

GnomAD4 genome AF: 0.0121 AC: 1843 AN: 152326 Hom.: 39 Cov.: 31 AF XY: 0.0114 AC XY: 852 AN XY: 74488

Gnomad4 AFR AF: 0.0419

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.000637 Hom.: 0

Bravo AF: 0.0141

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0418 AC: 184

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00407 AC: 494

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0045	T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.021	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.94	P;.
Vest4		0.56
MVP		0.92
MPC		0.27
ClinPred		0.13	T
GERP RS		3.3
Varity_R		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs74773083; hg19: chr1-1848197;