rs74773083

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-1916758-G-C
• chr1-1916758-G-T
• chr1-1916758-G-A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138705.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALML6	NM_138705.4	MANE Select	c.260G>C	p.Gly87Ala	missense	Exon 4 of 6	NP_619650.2	Q8TD86
	CALML6	NM_001330313.2		c.209G>C	p.Gly70Ala	missense	Exon 3 of 5	NP_001317242.1	B1AKR1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALML6	ENST00000307786.8	TSL:1 MANE Select	c.260G>C	p.Gly87Ala	missense	Exon 4 of 6	ENSP00000304643.3	Q8TD86
	CALML6	ENST00000378604.3	TSL:3	c.209G>C	p.Gly70Ala	missense	Exon 3 of 5	ENSP00000367867.3	B1AKR1
	CALML6	ENST00000462293.1	TSL:3	n.334G>C		non_coding_transcript_exon	Exon 2 of 3

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

GnomAD2 exomes AF: 0.00342 AC: 860 AN: 251110 AF XY: 0.00249

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 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

African (AFR) AF: 0.0450 AC: 1507 AN: 33480

American (AMR) AF: 0.00309 AC: 138 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52786

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111992

Other (OTH) AF: 0.00262 AC: 158 AN: 60386

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

African (AFR) AF: 0.0419 AC: 1741 AN: 41566

American (AMR) AF: 0.00497 AC: 76 AN: 15304

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: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68022

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0045	T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		5.1
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.021	D
Sift4G	Pathogenic	0.0010	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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs74773083; hg19: chr1-1848197;