6-25426540-G-A

Variant names:

• chr6-25426540-G-A
• rs9358856
• NM_017640.6:c.229G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017640.6(CARMIL1):​c.229G>A​(p.Val77Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,610,102 control chromosomes in the GnomAD database, including 17,584 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1522 hom., cov: 31)
  • Exomes 𝑓: 0.15 (16062 hom.)
• Consequence: CARMIL1 NM_017640.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.281
• Publications: 34 publications found

Genes affected

CARMIL1 (HGNC:21581): (capping protein regulator and myosin 1 linker 1) Involved in several processes, including actin filament network formation; plasma membrane bounded cell projection organization; and positive regulation of cellular component organization. Located in several cellular components, including lamellipodium; macropinosome; and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

CMAHP (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004101813).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017640.6. 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
	CARMIL1	NM_017640.6	MANE Select	c.229G>A	p.Val77Ile	missense	Exon 4 of 37	NP_060110.4
	CARMIL1	NM_001173977.2		c.229G>A	p.Val77Ile	missense	Exon 4 of 37	NP_001167448.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARMIL1	ENST00000329474.7	TSL:1 MANE Select	c.229G>A	p.Val77Ile	missense	Exon 4 of 37	ENSP00000331983.6
	CARMIL1	ENST00000461945.1	TSL:1	c.-21G>A		5_prime_UTR	Exon 4 of 9	ENSP00000489403.1
	CARMIL1	ENST00000700669.1		c.229G>A	p.Val77Ile	missense	Exon 4 of 37	ENSP00000515137.1

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20642 AN: 151170 Hom.: 1522 Cov.: 31

Gnomad AFR AF: 0.0854

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.170

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.140

Gnomad OTH AF: 0.141

GnomAD2 exomes AF: 0.162 AC: 40231 AN: 248160 AF XY: 0.163

Gnomad AFR exome AF: 0.0855

Gnomad AMR exome AF: 0.197

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.240

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.145 AC: 212028 AN: 1458814 Hom.: 16062 Cov.: 31 AF XY: 0.146 AC XY: 105941 AN XY: 725690

African (AFR) AF: 0.0844 AC: 2821 AN: 33410

American (AMR) AF: 0.189 AC: 8438 AN: 44576

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3822 AN: 26036

East Asian (EAS) AF: 0.220 AC: 8715 AN: 39582

South Asian (SAS) AF: 0.174 AC: 14954 AN: 85922

European-Finnish (FIN) AF: 0.183 AC: 9735 AN: 53324

Middle Eastern (MID) AF: 0.146 AC: 839 AN: 5756

European-Non Finnish (NFE) AF: 0.138 AC: 153675 AN: 1109960

Other (OTH) AF: 0.150 AC: 9029 AN: 60248

GnomAD4 genome AF: 0.136 AC: 20636 AN: 151288 Hom.: 1522 Cov.: 31 AF XY: 0.141 AC XY: 10431 AN XY: 73836

African (AFR) AF: 0.0853 AC: 3514 AN: 41190

American (AMR) AF: 0.170 AC: 2576 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 521 AN: 3468

East Asian (EAS) AF: 0.224 AC: 1154 AN: 5152

South Asian (SAS) AF: 0.181 AC: 868 AN: 4794

European-Finnish (FIN) AF: 0.186 AC: 1925 AN: 10344

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.140 AC: 9530 AN: 67876

Other (OTH) AF: 0.140 AC: 293 AN: 2100

Alfa AF: 0.139 Hom.: 6293

Bravo AF: 0.132

TwinsUK AF: 0.132 AC: 489

ALSPAC AF: 0.130 AC: 500

ESP6500AA AF: 0.0770 AC: 299

ESP6500EA AF: 0.144 AC: 1196

ExAC AF: 0.160 AC: 19328

Asia WGS AF: 0.178 AC: 622 AN: 3476

EpiCase AF: 0.142

EpiControl AF: 0.138

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.011
DANN	Benign	0.83
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.020	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.28
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.018
Sift	Benign	0.23	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.013
MPC		0.25
ClinPred		0.0011	T
GERP RS		-1.4
Varity_R		0.026
gMVP		0.077
Mutation Taster		=97/3	polymorphism (auto)

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: rs9358856; hg19: chr6-25426768; COSMIC: COSV61514777;